In one aspect, the present invention relates to methods and apparatuses for treating microcirculatory problems, including transient and reversible conditions that do no involve structural injury, as well as permanent or chronic conditions that do involve structural injury to the microcirculation. In another aspect, the invention relates to methods and apparatuses for augmenting normal microcirculation. In a related aspect, the invention relates to methods and apparatuses for treating conditions that involve osteonecrosis, compartment syndrome, edema, and skin flap survival.
In yet another aspect, the present invention relates to methods and devices for addressing cerebral edema, and to materials, such as catheters (including vetnriculosotomy catheters) and semipermeable membranes, for use in site specific treatment of tissues and tissue disorders.
A number of clinical conditions involve (e.g., are caused by and/or themselves cause) impaired circulation, and particularly circulation within interstitial spaces and within discrete, localized tissues. Among the more vexing examples of such circulatory afflictions are osteonecrosis (e.g., avascular necrosis), compartment syndrome, and edema (and in particular, cerebral edema).
A number of conditions involve poor blood supply to the bone, leading to bone necrosis. Avascular necrosis of the proximal femur, for instance, is the disabling end result of a variety of disease processes that can affect patients of all ages. There is no treatment presently available that can predictably alter the natural history of the disorder. Clinical and radiographic progression to femoral head collapse occurs in approximately 80 percent of cases, and 50 percent undergo total hip replacement within three years. Numerous techniques have been attempted aimed at promoting the early revascularization of the femoral head, with the goal of reversing the usual process of joint deterioration. These approaches include muscle pedicle transfer and vascularized bone grafts.
Other methods, including bone remodeling and fracture repair are. similar at the cellular level, and involve the coordinated delivery of a variety of cellular elements such as growth factors, such as transforming growth factor beta (TGF-beta), fibroblast growth factor (FGF) and bone morphogenetic protein. Several technical barriers to the treatment of AVN of the femoral head and neck include the limited blood supply of the site, difficult surgical access, and the accelerated progression of the disease due to biomechanical demands of walking on the hip joint.
Acute compartment; syndrome generally involves impaired circulation within an enclosed fascial space, leading to increased tissue pressure and necrosis of muscle and nerves. The soft tissue of the lower leg is contained within four compartments, each bounded by heavy fasciaxe2x80x94the anterior, lateral, superficial posterior, and deep posterior compartments. The anterior compartment holds the major structures for ankle dorsiflexion and foot and extension. Direct trauma, ischemia, or excessive, unaccustomed exercise can result in hemorrhage and swelling inside the anterior compartment. This swelling will increase pressure on the nerves, veins and arteries inside the compartment. Without arterial circulation, muscle cells will die. In addition, the prolonged compression of nerves can destroy their ability to function.
The neurovascular compression continues to worsen in the following symptoms: weakness or inability to dorsiflex the foot or extend the great toe, decreased ability of the peroneal tendon to evert the foot, and marked itching or prickling sensations in the web between the first and second toe or over the entire dorsal area of the foot. These symptoms must be identified quickly, since misdiagnosis can lead to permanent neuromuscular damage and physical disability.
Diagnosis involves clinical symptoms such as pain and swelling, and signs such as tense compartment pain on passive stretching, parathesia and decreased pulse, and increases in intracompartmental pressure. Once diagnosed, the injury requires immediate decompression through surgical release of the fascia covering the area. Others suggest treatment means include the use of a sympathetic blockade, hyperbaric oxygen therapy, and treatment with mannitol and/or alloperinol.
The characteristics of acute tissue edema are well known, and the condition continues to be a clinical problem, particularly since edema can be detrimental to the tissue as a result of disruption of the microcirculation. Tissue swelling results in increased diffusion distances, which in turn decreases interstitial nutrient delivery. Irreversible disruption of the microcirculatory system can occur as a result of unresolved acute injury. Resolution of tissue edema is problematic since natural mechanisms by which edema resolves are also affected by the edema. Edema compresses venules and lymphatic vessels, and inflammation makes lymphatic vessels hyperpermeable. Pharmacologic treatment is often not effective since blood borne agents have difficulty reaching their target tissue.
Cerebral edema (also known as brain swelling), includes vasogenic cerebral edema (most common form of edema) which manifests itself in the form of increased permeability of small vessels (breakdown of blood-brain barrier) and the escape of proteins and fluids into extracellular space, especially of white matter. Other forms of cerebral edema include cytotoxic cerebral edema (cellular brain edema) and interstitial edema.
Cerebral edema can be caused by ischemia, loss of oxygen, or focal disruption or loss of blood supply such as stroke. In the case of stroke, the specific area must be treated early to prevent further damage. The diagnosis of cerebral edema is based on changes in mental status, imaging, and measurement of intracranial pressure. Conventional treatment of cerebral edema is controversial. Some practictioners insist on keeping the blood pressure high to overcome high intracranial pressure, while others keep the blood pressure low in the hopes of limiting intracranial pressure. Opening the skull generally cannot be done to relieve pressure, because the brain tissue would herniate out the opening causing significant tissue damage. Giving intravenous treatments is also not effective because the bra in microcirculation is disrupted so deilivery to the brain is impaired.
Neurologic damage initiated by traumatic brain injury (TBI) continues to evolve over a period of hours to days following injury, due to deleterious delayed or secondary insults. The formation of cerebral edema, which, in turn, can lead to elevated intracranial pressure (ICP), is one of the most prevalent secondary insults serving to increase patient morbidity and mortality after TBI. ICP rises rapidly with the addition of a small intracranial fluid volume, due to the rigid and relatively inflexible nature of the skull. Complicating factors include relative noncompressability and constant volumes of brain tissue, blood, and cerebrospinal fluid (CSF) within the craniospinal intradural space. Brain swelling leading to dangerously elevated ICP develops in 40-50% of TBI patients with a Glascow Coma Scale (GCS) of 8 or less, and higher ICP levels have been repeatedly shown to lead to poor prognosis or outcome.
Monitoring of ICP is considered appropriate for all patients with severe TBI. While the placement of an ICP monitor is invasive, the benefits of ICP monitoring are felt to offset this factor, carry a relatively small risk of complications (e.g., infection, hemorrhage, malfunction, obstruction or malposition), and rarely result in increased patient morbidity. Percutaneous devices (e.g., ventriculostomy catheters) for use in monitoring ICP monitoring are commercially available in a variety of styles and from a number of sources. Such devices are commonly placed within the cerebral ventricles, where they enable accurate and reliable monitoring of ventricular pressure and can be used for the therapeutic convective drainage of CSF.
CSF drainage is described as a potentially effective method of lowering ICP, particularly when ventricular size has not been compromised. CSF drainage typically requires penetration of the brain parenchyma with a ventricular catheter. A variety of ventricular catheters are available for such purposes, e.g., the xe2x80x9cMoniTorrxe2x80x9d product available from CNS, Inc. As fluid is removed, however, brain swelling often progresses to the point where the ventricular system is compressed and the ability to drain CSF can be compromised. This may be exacerbated by overdrainage, leading to the ventricular walls or the choroid plexus actually collapsing in a manner that occludes the orifices of the catheter.
The therapeutic efficacy of convective CSF drainage by conventional ventriculostomy catheters, therefore, is limited. It has been shown that CSF can be removed from the ventricles in a manner that reduces the overall intracranial volume, and thus pressure. The fluid, however, is removed from the ventricle, not from the edematous brain tissue. Once the ventricular fluid has been removed, there is typically no further reduction in ICP. Also, ventriculostomy catheters can become occluded with tissue debris and clots during convective fluid removal.
In addition to the occasional therapeutic drainage of CSF via ventricular catheters there are three primary medical treatment strategies used in attempts to control cerebral edema elevated ICP in patients with severe TBI. As briefly outlined below, it can be seen that each of these therapeutic strategies is a xe2x80x9cdouble-edged swordxe2x80x9d since each treatment is typically associated with potential adverse consequences and each has limited efficacy.
Hyperventilation: Prophylactic hyperventilation of TBI patients is currently questioned since it has been reported to worsen outcomes, does not consistently reduce ICP, and may cause loss of autoregulation and potentiate secondary ischemia due to its actions on reducing cerebral blood flow.
Mannitol: This osmotic diuretic is currently the most widely used, and probably the safest, treatment for short-term control of elevated ICP in patients with TBI. Although it has become the cornerstone for control of elevated ICP after severe TBI, mannitol administration is not without risks. Careful monitoring and maintenance of serum osmolarity below 320 mOsm is needed to reduce the risk of acute renal failure, and the latter risk is potentiated in patients with sepsis or preexisting renal disease. Although the use of mannitol affects osmolarity within the site, this approach is not site-specific, rather, it is systemically administered. Since this approach is also chemically based, rather than device based, it does not employ a device that is itself provides an osmotic barrier.
Barbiturates: Prophylactic barbiturate therapy is currently discouraged, due to variable and unpredictable positive effects on ICP. Barbiturate therapy is now typically used only in hemodynamically stable patients with intracranial hypertension/elevated ICP that is refractory to all other therapeutic interventions.
To date, osmotic fluid shifts in the course of TBI has received relatively little attention in the literature. Recent animal studies include one regarding CSF osmolality and the other regarding brain tissue osmolality (See C. Onal, et al., Acta Neurochir (Wien) 139:661-669 (1997). CSF osmolality was found to increase after a focal freeze injury in rats. CSF osmolality was found to increase from 277 mmol/kg to 348 mmol/kg at six hours after injury. CSF osmolality returned to 270 mmol/kg by 24 hours after injury. Interestingly, cerebral water content also increase at six hours, but remained elevated at 24 hours. Blood-brain barrier permeability also increased markedly at six hours and improved but remained elevated at 24 hours. Investigators in this study then went on to give intraventricular albumin to reduce the edema.
In the brain tissue study by Mori et al. J. Neurotrama 15:30 (1998), the osmolality was found to increase after cerebral contusion in a rat model. They found normal brain tissue osmolality to be 310 mmol/kg. Thirty minutes after injury, the tissue osmolality increased to 367 mmol/kg, and further increased to 402 mmol/kg at six hours. The investigators also compared ion concentration to total osmolality. On a separate topic, Janese (U.S. Pat. No. 4,904,237) describe the manner in which cerebral edema (i.e. water accumulation in brain tissue) constitutes one of the most severe and life threatening situations that occurs after traumatic brain injury (TBI) in humans. While edema can be controlled in many patients by the use of drug treatments, there are many patients for whom such treatment is not effective.
On a separate subject, Kanthan et al., J. Neuroscience Meth. 60:151-155 (1995), describe a method of in vivo microdialysis of the human brain, which method involves a xe2x80x9cclosedxe2x80x9d technique in which a microdialysis probe and sheath are passed through a Codman bolt. Dialysate is withdrawn for periodic analysis. Similarly, Lehman et al., Acta Neurochir.[Suppl.], 67:66-69 (1996), describe a microdialysis probe for minimally invasive measurements of various products and metabolites in the brain. A number of other references describe various aspects and observations regarding the osmolar nature of brain fluids. See, for instance, Hossman, pp. 219-227 in xe2x80x9cDynamics of Brain Edemaxe2x80x9d, Pappius, et al., eds. (1976); Hatashita, et al., pp. 969-974 in xe2x80x9cIntracranial Pressure VIIxe2x80x9d, Hoff et al; eds.; and Hoff et al., pp 295-301 in xe2x80x9cOutflow of Cerebrospinal Fluidxe2x80x9d (1989).
Yet other medical devices have been described which employ semipermeable membranes adapted to be implanted on a transitory basis, such as those presently used for xe2x80x9cintracerebral microdialysisxe2x80x9d in order to monitor rapid, ongoing chemical changes in the interstitial fluid (ISF). Such devices have been described as being potentially useful for examining neurochemical changes in the brains of patients with neurological disorders. Although analysis of brain ISF in this manner is still considered an invasive procedure, investigators have now demonstrated efficacy and safety of the technique in clinical situations. It would appear that several clinical research centers have begun using intracerebral microdialysis for monitoring the ISF within the past several years, and such monitoring has been employed in patients with TBI. To date, however, Applicant is unaware of any description of the use of such dialysis techniques or apparatuses in the treatment of cerebral edema or ICP.
In the course of inserting microdialysis probes into brain parenchyma, in order to monitor neurochemical alterations in patients, it has been found that there is minimal trauma to brain tissue and that complications are extremely rare. However, most, if not all, current microdialysis procedures rely on the slow, pump-driven infusion of dialysis fluid which travels through inlet lines past the dialysis fiber and then through outlet lines to enable collection of the dialysate. The dialysis probes used in such procedures are generally of rigid construction, to enable passage into brain tissue. The procedures themselves typically result in only a small percent xe2x80x9crecoveryxe2x80x9d of neurochemicals or other molecular entities, for assay, since the procedures rely on the diffusion of chemicals from ISF to the dialysis fluid.
Investigators also commonly insert apparatuses into the brain ventricles, for a variety of reasons. Osterholm, for instance (U.S. Pat. Nos. 4,378,797, 4,445,500, 4,445,886, 4,758,431, and 4,840,617 ) describes a cerebral catheterization apparatus for delivering oxygenated nutrient to of from the CSF of a patient suspected of suffering from ischemia (stroke). The apparatus includes a catheter for providing an oxygenated nutrient, in the form of a synthetic CSF, to the ventricle. In view of the need to deliver (e.g., perfuse) such a nutrient to the brain quickly after stroke, this particular patent is directed toward a catheterization apparatus intended to be used by paramedics and emergency room personnel to insert a cerebral perfusion catheter into the left and right lateral brain ventricles of the patient.
The use of skin flaps has gained increased acceptance and use in the course of reconstructive and other forms of surgery. These techniques, however, continue to be plagued by problems having to do with survival of the skin flaps, which in turn, is believed to rely, at least in part, on efficient revascularization of the site. A number of approaches have been considered or evaluated for improving skin flap survival. See, for instance, Waters, et al., which provides a comparative analysis of the ability of five classes of pharmacological agents to augment skin flap survival in various models and species, in an attempt to standardize skin flap research. (Annals of Plastic Surgery. 23(2):117-22, 1989 August).
On a separate subject, the development of methods and apparatuses for tissue microdialysis began at least as early as the early 1960""s with the work of Gaddum and others. To date, microdialysis has been used primarily, and with increasing frequency, in the neurosciences, as a means of assaying the interstitial space. In such applications the delivered solution is typically isotonic in order to avoid producing an osmotic gradient and resulting fluid shift. See, generally, Lonroth, et al. , J. Intern. Med., 1990 May;227(5):295-300, xe2x80x9cMicrodialysisxe2x80x94A Novel Technique for Clinical Investigationsxe2x80x9d; Johansen, et al. Pharmacotherapy 1997 May;17(3):464-481, xe2x80x9cThe Use of Microdialysis in Pharmacokinetics and Pharmacodynamicsxe2x80x9d; and Cimmino et al., Diabetes Metab. 1997 April; 23(2):164-170, xe2x80x9cTissue Microdialysis: Practical and Theoretical Aspectsxe2x80x9d.
A limited number of references describe the use of microdialysis to deliver substances such at therapeutic agents. Lehmann et al., Acta Neurochir. Suppl., 67:66-69 (1996), describe a microdialysis probe adapted for entry into the parenchyma in order to measure various analytes, the probe being described as useful for possible xe2x80x9ctherapeutic applicationsxe2x80x9d. Similarly, Yadid, et al., Am. J. Physiol. 265:R1205-R1211 (1993), describe a modified microdialysis probe for sampling extracelluar fluid and delivering drugs for use in studying the local release and metabolism of neurotransmitters in vivo.
A limited number of other references describe the use of microdialysis to remove interstitial fluid for diagnostic purposes, as described, for instance in Linhares et al., Anal. Chem. 64:2831-2835 (1992). Recent articles have described the use of a hollow fiber catheter to perfuse the catheter with a hypertonic solution in order to intentionally produce a fluid shift and reduce tissue edema. See, for instance, Odland, et al. xe2x80x9cReduction of Tissue Edema by Microdialysisxe2x80x9d Arch. Otolaryngol. Head Neck Surg, Vol. 121, pp. 662-666 (1995), which describes the use of a test device having catheters connected by afferent segments of tubing to an infusion pump providing a hypertonic solution of inulin in saline.
To Applicant""s knowledge, however, there is no present teaching, let alone clinically acceptable approach for the application of tissue microdialysis in site specific therapy, or in particular, a microdialysis apparatus useful for prolonged periods, difficult sites, and in clinical settings.
In turn, current therapies for treating elevated ICP and cerebral edema, in humans with severe traumatic brain injury, have limited efficacy and continue to be associated with serious risks (particularly with prolonged use). In some patients, cerebral edema simply remains untreatable or nonresponsive to treatment. What is clearly needed are methods and related devices and systems for use in relieving ICP, particularly in a manner that optimizes the ability to employ conventional techniques and apparatuses, in new and different combinations, in order to improve overall patient outcome.
The present invention provides a method and related system for use in site specific therapy of a tissue site. In a preferred embodiment, the invention provides a system comprises one or more catheters adapted to be positioned within the tissue site and a delivery/recovery mechanism for employing the catheter(s) to control the movement of bulk fluids and/or active fluid components within or between tissue portions or adjacent tissues in a manner that achieves a therapeutic effect. More preferably, the tissue site comprises an anatomic site within the body containing one or more fluids in latent or actual fluid communication, the fluids, in turn, each containing one or more active fluid components selected from the group consisting of biologically active molecules and osmotically active molecules.
In a corresponding method, the fluid movement can be used to affect the osmolar nature of a remote first fluid by altering the osmolar nature of a second fluid in osmotic ommunication with the first fluid, and/or it can be used to effect the movement of biologically active molecules between adjacent healthy and diseased portions of the same tissue. In a particularly preferred embodiment, the catheter(s) comprise one or more semipermeable microcatheters, adapted to effect the movement of fluid or fluid components within the tissue site by microdialysis within the tissue site.
The term xe2x80x9ctissue sitexe2x80x9d, as used in this respect, will refer to an anatomic location or organ within the body containing one or more fluids in latent or actual fluid communication, the fluids, in turn, each containing one or more components such as biologically. or osmotically active molecules. The method and system involve the deliberate and controlled, and optionally selective, movement of fluids and/or the active fluid components, in a direct or indirect fashion, within or between tissue portions or adjacent tissues. Such fluid movement can be used, for instance, to affect the osmolar nature of a remote first fluid by altering the osmolar nature of a second fluid in osmotic communication with the first. Such fluid movement can also be used, for instance, to effect the movement of agents between adjacent healthy and diseased portions of the same tissue.
The catheter assemblies, in turn, can be provided in any suitable form, including the use of one or more individual catheters. In certain applications one or more of the catheters within an assembly are preferably provided in the form of semipermeable microcatheters, which in turn are adapted to permit dialysis to be performed within the tissue site.
In one embodiment, therefore, the present application provides an apparatus and method for performing site specific microtherapy, a preferred embodiment of the apparatus comprising one or more catheters (optionally including semipermeable microcatheters) dimensioned to be positioned within a tissue site, the catheters comprising one or more surfaces for delivering fluid to the tissue site and one or more surfaces for removing fluid from the tissue site, the catheters being adapted for fluid communication with a pump reservoir or other mechanism for the delivery and/or recovery of fluid or fluid components. Optionally, and preferably, the apparatus includes such a pump reservoir as a component part.
In a further preferred embodiment, the apparatus provides an outflow circuit for delivering fluid (and/or solutes) to the tissue site and an inflow circuit for removing fluid (and/or solutes) from the tissue site, in combination with a manifold and associated pump system for controlling and directing the flow of fluid within the catheter(s). In one such embodiment, the outflow and inflow circuits each employ one or more catheters to recover and deliver fluid (optionally containing solutes such as biological agents) between sites of healthy and diseased or injured tissue. In another preferred embodiment, the outflow and inflow circuits are provided in the form of separate and substantially parallel recovery and delivery catheters, where they cooperate to provide convective interstitial flow within the tissue site.
Applicant has found that the distribution of fluids within or between portions of a tissue, including the delivery of fluids and any solutes contained therein, can be significantly enhanced by the present apparatus, which can serve to artificially replicate the hydrostatic forces and/or solute delivery characteristics of the microcirculatory system. In such a preferred embodiment the present invention employs microfibril technology to deliver and/or remove fluid, solutes, or specific agents to and/or from a tissue space. In particular, the apparatus permits the infusion of fluids and/or therapeutic agents, and the corresponding removal of tissue fluids and/or biological factors, with the optional ability to simultaneously monitor physiologic parameters. In turn, the invention further provides a commercially viable in vitro tissue engineering technique based on the principle of microdialysis.
The apparatus and method of the present invention can be used for a variety of purposes in the course of providing artificial microcirculation, including for instance, for replicating, repairing, or augmenting circulation inside or outside of the body. In turn, the present invention can be used for a variety of applications, including to treat reperfusion injury or deliver toxic agents directly to a tissue site (inter alia, to avoid systemic toxicity), and for the delivery of poorly diffusible molecules to the interstitum. In particularly preferred embodiments, the apparatus and method of this invention are used to treat clinical conditions that include cerebral edema, stroke, osteoporosis, ischemic osteonecrosis (e.g.; avascular necrosis (xe2x80x9cAVNxe2x80x9d) of the femoral head), compartment syndrome, skin flap failure, reperfusion injury, and inflammation in fixed spaces. The apparatus and method of the invention can also be used for the preparation of bone and soft tissue grafts.
A preferred apparatus employs a hydrostatic or osmotic gradient, established by the use of one or more suitably placed and configured catheters, to affect tissue metabolism or fluid flow in large or small sites. The microdialysis system solves the problem of treating focal tissue sites when a) there is inadequate local tissue microcirculatory system to perfuse the tissues, b) systemic toxicity of the agent is a factor, c) the agents to be delivered or removed are large, and d) any combination of the above. The apparatus can be provided as a single catheter, employing either diffusional, osmolar, or hydrostatic forces, or a plurality of catheters having one or more dedicated delivery and recovery catheters, or portions thereof, that employ similar forces.
In another preferred embodiment, the present invention provides a system, including a catheter apparatus, and related method for performing site-specific therapy at a tissue site having first and second fluids separated by an osmotic barrier, wherein the tissue site exhibits edema brought about by accumulation of the first fluid. The system comprises an apparatus that comprises:
a) one or more catheters adapted to be positioned in fluid communication with the second fluid of the tissue site, and
b) a fluid delivery/recovery mechanism for delivering and/or recovering fluid components (e.g., a component containing water and permeant solutes or the impermeant solute component), to and/or from the tissue site in a manner that affects the osmolarity of the first and/or second fluids in order to reduce edema.
In a particularly preferred embodiment, the system and related method are adapted for treating ICP associated with cerebral edema, and the system comprises an apparatus that comprises:
a) one or more catheters adapted to be positioned in fluid communication with the cerebrospinal fluid within a ventricle in the brain, and
b) a fluid delivery/recovery mechanism for delivering and/or recovering fluid components to and/or from the tissue site in a manner that affects the osmolarity of either or both fluids in a manner that reduces edema.
A further preferred embodiment is adapted for situations in which the edema involves an increase in pressure brought about by the accumulation of a first fluid (interstitial and/or intracellular fluid within the brain), and the system comprises an apparatus that comprises:
a) one or more semipermeable microcatheters adapted to be positioned in fluid communication with cerebrospinal fluid within a ventricle in the brain, and
b) a fluid delivery/recovery mechanism for delivering and/or recovering fluid components to and/or from the CSF in a manner that affects the osmolarity of either the CSF or corresponding brain fluids in a manner that reduces edema. In a particularly preferred embodiment, the system can be used in a method that involves either delivering impermeant (i.e., osmotically active) solutes to, or removing solute from, the CSF, in order to begin a cascade of events leading, eventually, to a reduction in edema.
A corresponding method of the present invention includes the steps of:
a) providing a system comprising an apparatus as described above,
b) positioning the apparatus within the second fluid of a tissue site exhibiting edema, and
c) employing the fluid delivery/recovery system to deliver and/or recover fluid components to and/or from the second fluid in a manner that subtstantially alters the osmolarity of the first fluid in order to reduce edema.
While not intending to be bound by theory, the present system is based, at least in part, on the Applicant""s premise that certain tissue sites exhibiting edema can be viewed as two distinct fluids, having the potential for osmotic disparity between them. That disparity provides an opportunity for therapeutic intervention. The first and second fluids may, individually, be hyper- , hypo-, or isoosmolar, either with regard to each other and/or to their original, non-edema state. In edema, for instance, the first and second fluids can establish an osmotic equilibrium with respect to each other, e.g., in which there is no net flux of solvent between them, even while the volume of the first fluid remains increased, causing edema at the tissue site.
The invention, therefore, provides means for affecting that osmotic disparity in such a manner that the volume of the first fluid is decreased in order to alleviate edema. The word xe2x80x9caffectsxe2x80x9d, as used in this context, refers to any influence or control over the absolute or relative osmolar status of the first or second fluids, e.g., by affirmatively altering the osmolar nature of one or both fluids, or by maintaining both fluids static under conditions where they would have tended to change. From one perspective, the invention provides a method for altering the osmotic relationship of the two fluids in a manner that permits a desired result in the first fluid to be achieved indirectly, by altering the osmotic nature of the second fluid. The osmolar relationship between the two fluids can also be altered, or maintained static, by altering characteristics of the barrier itself (i.e., the membranes separating first fluid from the second fluid), to provide the same or similar effect. For instance, the barrier can be treated in a minimally invasive fashion (as with the delivery of surfactants, or mechanically) to change its effective molecular weight cutoff, and in turn, the definition (and therefore number) of impermeant solutes in each affected fluid.
Such a system can be used to recover the solvent component of the second fluid, that is, water and solutes that freely pass the semipermeable barrier (alternatively referred to herein as xe2x80x9cpermeant solutesxe2x80x9d or xe2x80x9cinactive osmolesxe2x80x9d). This solvent component can be removed in an amount sufficient to effectively raise the concentration of remaining impermeant solutes in the second fluid. The increased impermeant solute concentration in the second fluid (e.g., ventricular CSF), in turn, causes solvent from the first fluid to cross the osmotic barrier into the second fluid. The loss of solvent from the first fluid, in turn, effectively increases the osmolarity of the remaining interstitial fluid, which in turn causes compensatory water/electrolytes to be drawn from surrounding cells in an amount sufficient to lessen the swelling (edema) in those surrounding tissues, and/or to reduce the pressure exerted by the tissue upon other tissues. The permeant component of CSF can be removed and/or permitted to drain from the ventricle by natural means, through arachnoid granulations, finally becoming absorbed in the blood.
Using rat models and similar systems Applicant has found, for instance, that there is a increase in CSF osmolarity after head trauma, which is consistent with the idea that osmotic relationships differ between the fluids following injury. Applicant has further found that microdialysis fibers, when tested in various fluid solutions (ranging from saline to artificial CSF), were indeed able to extract the solvent component in a manner that alters osmolarity. Applicant has also evaluated the use of various types of microdialysis fibers with preserved CSF from TBI patients.
In a preferred embodiment the method and system are site specific, in that they can be used to alter the osmolar relationship between fluids within a particular tissue site. The method and system are also optionally highly selective (e.g., by the selection and use of osmoles of specific sizes or concentrations).
In turn, the preferred method and system have an indirect effect, in that they can be used to achieve a result in a remote (first) fluid, for instance, by lessening its volume, and in turn, its pressure. This indirect effect can be achieved by direct contact with (and the affirmative manipulation of) a second fluid, which is directly or indirectly separated from the first fluid by an osmotic barrier. The method and system can achieve such results in any suitable manner, e.g., by altering the absolute and/or relative volumes or osmolarities of one or more fluids, and/or by simply controlling or maintaining the volumes and/or osmolarities in order to prevent further edema.
By way of example, the delivery/recovery step can involve the delivery of fluids and/or osmotic agents, to or from the first and/or second fluids. Generally, in situations where either or both fluids can be accessed within a tissue site, and where edema is due to increased volume of the first fluid, site-specific treatment options include: 1) recovering solvent from the second fluid; 2) delivering osmoles to the second fluid; 3) recovering osmoles from the first fluid; and/or 4) delivering solvent to the first fluid.
In the case of cerebral edema, however, the present invention provides apparatuses that can be used to access either of the two compartments (and in either of the two fluids) making up the tissue site, namely, parenchymal probes for accessing the first fluid and ventricular apparatuses for accessing ventricular CSF. In the latter embodiments, the method and system of the present invention, in turn, will typically involve either the removal of solvent from the second fluid or the delivery of osmoles to the second fluid. In either case, the net effect is an increase in the osmolarity of the second fluid, followed by the cascade of events described herein, including the diffusion of solvent from the first to second fluids.